JP2018095593A - Lyophilized preparation and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a bortezomib preparation that has excellent storage stability and can be reconstituted into water in a short time.SOLUTION: The present invention provides a lyophilized preparation containing bortezomib, arginine, and hydroxy dicarboxylic acid and/or a salt thereof, and a method for producing the same.SELECTED DRAWING: None

Description

  The present invention relates to lyophilized formulations. Specifically, the present invention relates to a stable and easily reconstituted lyophilized formulation containing bortezomib and a method for producing the same.

  Bortezomib has the following formula:

It is an antineoplastic agent developed by Millennium Pharmaceuticals as a molecular target drug that selectively and reversibly inhibits the proteasome and exhibits an antitumor action (Patent Document 1). Bortezomib was approved for the indication of multiple myeloma in the United States in 2003, and subsequently approved in more than 100 countries around the world, including Japan, the United Kingdom, and Germany, and is currently marketed under the brand name Velcade®.

Bortezomib has a problem of stability because it has an alkylboronic acid structure, and also has a problem that it is not highly soluble in water. Therefore, research has been conducted on a freeze-dried preparation of bortezomib that is more stable than conventional preparations and easily reconstituted in water.
Patent Document 2 describes a method for producing a freeze-dried compound by freeze-drying bortezomib with mannitol, a composition obtained by the production method, and a mannitol ester of bortezomib obtained by the production method. Alkylboronic acid has the property that it takes an equilibrium state with an ester in the presence of alcohol, and becomes an ester when water is reduced, and the ester is hydrolyzed and alkylboronic acid is freed when water is increased. Yes. The invention of Patent Document 2 utilizes this property and is applied to a commercially available Velcade (registered trademark) lyophilized preparation. However, the freeze-dried preparation obtained in Patent Document 2 is not fully satisfactory in terms of storage stability or reconstitution time in water.

Patent Document 3 discloses a freeze-dried preparation of bortezomib or a derivative thereof characterized by adding cyclodextrin. Example 18 describes the preservation stability of the freeze-dried bortezomib as the HPLC purity after 6 months at 40 ° C./75% RH decreased to 89.3%.
Patent Document 4 discloses a lyophilized preparation containing bortezomib and tromethamine. Tables 2-5 list the storage stability and reconstitution time of the lyophilized formulation. The lyophilized formulation of Example IV has a total related substance of 2. It has increased greatly to 98%.

Patent Document 5 describes a freeze-dried preparation in which glycine, boric acid or dextrin is added to bortezomib. [0066] In the freeze-dried preparation added with glycine and boric acid, the total of impurities A, B and C was 0.8 to 1.21% in the storage stability test after 3 weeks at 55 ° C. It is described. Patent Document 5 does not describe arginine.
Patent Document 6 discloses a lyophilized preparation containing bortezomib and an amino acid. As the amino acid, an amino acid having a hydroxyl group or a mercapto group is described as preferable, and in the Examples, a lyophilized preparation containing serine, threonine or cysteine is described as a preferable example. On the other hand, those containing glycine, phenylalanine or tyrosine are described as being incapable of solution or being reconstituted after lyophilization. Patent Document 6 does not describe arginine.

Patent Document 7 describes an ester of bortezomib and tartaric acid (Claim 1), and the ester is obtained as a solid in Examples. However, there is a problem that the reconstitution time of the ester is 120 seconds or more (Example 19), which is very long.
Patent Document 8 describes an ester of a boronic acid compound such as bortezomib with an α- or β-hydroxy acid (Claim 1). In the examples, esters with many acids such as citric acid, salicylic acid, lactic acid, tartaric acid and mandelic acid are obtained as crystals or solids. Patent Document 8 does not describe at all the stability and reconstitution time of the ester obtained in the example. For example, the ester with tartaric acid of Example 26 is the same as the ester with tartaric acid obtained in Patent Document 7. It seems that the reconstruction time is very long because it is considered equivalent. In Examples 46 to 49 of Patent Document 8, a boronic acid compound, citric acid and glycine are dissolved in t-butanol and water to obtain a freeze-dried product. However, the stability and reconstitution time are not described.
As described above, the conventionally known lyophilized formulations of bortezomib are still not sufficient in terms of storage stability or reconstitution time in water.

Japanese Patent No. 3717934 Japanese Patent No. 4162491 Special table 2012-52295 Japanese Patent No. 5689816 WO2012 / 047845 CN103142509 WO2014 / 023647 Special table 2011-524903

  The problem to be solved by the present invention is to provide a novel formulation of bortezomib with excellent storage stability and a short time for reconstitution into water.

As a result of intensive studies, the present inventors have surprisingly found that a formulation obtained by adding arginine and hydroxydicarboxylic acid as a stabilizer to bortezomib in combination with lyophilization is excellent in stability, It has been found that reconfiguration also proceeds easily, and the present invention has been completed.
That is, the present invention is as follows.

[1] A freeze-dried preparation containing bortezomib, arginine, and hydroxydicarboxylic acid and / or a salt thereof.
[2] The lyophilized preparation according to [1], wherein the hydroxydicarboxylic acid is tartaric acid or citric acid.
[3] The lyophilized preparation according to [1] or [2], wherein the weight ratio of bortezomib and arginine is 1: 1.5 to 1:15.
[4] The freeze-dried preparation according to any one of [1] to [3], wherein the solution has a pH of 3.5 to 8 when dissolved in 3 mL of physiological saline per 3 mg of bortezomib.
[5] A method for producing a freeze-dried preparation, comprising a step of freeze-drying a solution containing bortezomib, arginine and dihydroxydicarboxylic acid and / or a salt thereof.
[6] The method for producing a lyophilized preparation according to [5], wherein a solution using only water as a solvent is used.

  The freeze-dried preparation of the present invention has excellent storage stability and a short reconstitution time into water.

Hereinafter, the present invention will be described in detail.
1. Lyophilized formulation The lyophilized formulation of the present invention is a lyophilized formulation comprising bortezomib, arginine, and hydroxydicarboxylic acid and / or a salt thereof. One feature of the lyophilizing agent of the present invention is that arginine and hydroxydicarboxylic acid are used in combination as stabilizers.
As “arginine”, any of L-form, D-form and racemic form can be used, and L-form is preferred. Arginine may be in the form of a salt. Examples of the salt include hydrochloride, sulfate, phosphate and the like. Arginine and its salts also include their hydrates.
The amount of arginine added is such that the weight ratio of bortezomib to arginine is, for example, 1: 1.5 to 1:15, preferably 1: 1.7 to 1: 13.3. More preferably, the amount is 1: 3.3 to 1:12, and more preferably, the amount is 1: 6.7 to 1:11. Addition of arginine improves the storage stability of bortezomib and shortens the reconstitution time into water.

Examples of the “hydroxydicarboxylic acid” include tartaric acid, citric acid, isocitric acid, malic acid, tartronic acid (2-hydroxymalonic acid), trihydroxyglutaric acid and the like. Preferable examples include tartaric acid and citric acid. Examples of the salt of “hydroxydicarboxylic acid” include alkali metal salts such as sodium salts and potassium salts, alkaline earth salts such as magnesium salts and calcium salts, amine salts, and salts of basic amino acids. Hydroxy dicarboxylic acids and salts thereof also include hydrates thereof.
By adding hydroxydicarboxylic acid, the basicity of arginine is neutralized to an appropriate pH described later, the storage stability of bortezomib is improved, and the reconstitution time into water is shortened.

  As content of hydroxy dicarboxylic acid, the quantity which neutralizes the basicity of arginine and makes it suitable pH mentioned later is mentioned. For example, when tartaric acid is used as the hydroxydicarboxylic acid, the weight ratio of arginine to tartaric acid and / or a salt thereof is, for example, 1: 0.3 to 1: 1, preferably 1: 0.2. An amount of ˜1: 0.7 is mentioned, and an amount of 1: 0.3 to 1: 0.5 is more preferred. For example, when citric acid is used as the hydroxydicarboxylic acid, an amount in which the weight ratio of arginine to citric acid and / or a salt thereof is, for example, 1: 0.3 to 1: 1 is exemplified, and preferably 1: 0. An amount of 4 to 1: 0.9 is mentioned, and an amount of 1: 0.45 to 1: 0.8 is more preferred.

The freeze-dried preparation of the present invention preferably has a pH of an injection prepared by dissolving in 3 mL of physiological saline per 3 mg of bortezomib, for example, 3.5-8. A more preferable pH is 4 to 8, still more preferably 4.5 to 7, and particularly preferably 5 to 7.
In order to adjust to the above pH, a “pH adjusting agent” can be further added. Examples of the pH adjuster include the above hydroxydicarboxylic acids; alkali hydroxides such as sodium hydroxide and potassium hydroxide; alkali carbonates such as sodium carbonate and potassium carbonate; alkali hydroxides such as magnesium hydroxide and calcium hydroxide. Earths; amines; basic amino acids and the like.

To the lyophilized preparation of the present invention, an isotonic agent, an additive, a surfactant, or the like can be further added as necessary.
Examples of the isotonic agent or additive include sodium chloride, mannitol, lactose, sucrose, glycine, maltose, trehalose, cyclodextrin, dextran, inositol, sorbitol, albumin, calcium lactobionate and the like.
Examples of the surfactant include polyvinylpyrrolidone, polysorbate, sorbitan ester, polyethylene glycol ether, saturated polyglycolized glyceride, fatty acid ester of polyethylene glycol, polyethylene / propylene glycol copolymer, polyethylene glycol stearate, d-α-toco Examples include ferryl polyethylene glycol succinate.

2. Production of freeze-dried preparation The freeze-dried preparation of the present invention can be produced, for example, as follows.
Bortezomib, arginine, and hydroxydicarboxylic acid and / or a salt thereof are dissolved in water alone or a mixed solvent of an organic solvent and water. Bortezomib, arginine and hydroxydicarboxylic acid and / or salt thereof can be dissolved separately and then mixed. After adjusting the volume of the obtained solution to a certain amount with water, it is sterilized and filtered, filled into a vial so as to be a certain amount of bortezomib, and lyophilized to obtain the lyophilized formulation of the present invention. obtain.
Dissolution of bortezomib, arginine and hydroxydicarboxylic acid and / or a salt thereof in water alone or an organic solvent and water in a mixed solvent is performed, for example, at 10 to 30 ° C, and preferably at 15 to 25 ° C. When these are separated and dissolved, it is carried out at a similar temperature.

In the freeze-drying of bortezomib and mannitol described in Patent Document 2, an organic solvent such as t-butanol is used. Surprisingly, when hydroxydicarboxylic acid and / or a salt thereof is used, A solution can be prepared using only as a solvent. Dissolving with only water without using an organic solvent can reduce the environmental burden, which makes production very advantageous.
Examples of water in which bortezomib, arginine and hydroxydicarboxylic acid and / or a salt thereof are dissolved include water used for medical treatment, and for example, water for injection is used. When bortezomib, arginine and hydroxydicarboxylic acid and / or a salt thereof are dissolved in water, the amount of the water is, for example, 10 parts per 1 part by weight in total of bortezomib, arginine and hydroxydicarboxylic acid and / or a salt thereof. -200 weight part is mentioned, Preferably 15-50 weight part is mentioned.

In the case of using an organic solvent, examples of the organic solvent include organic solvents that are miscible with water and removed by lyophilization. Specific examples include alcohols such as t-butanol, methanol, ethanol and 2-propanol, ethers such as acetonitrile, 1,4-dioxane and tetrahydrofuran, and ketones such as acetone, 2-butanone and methyl isobutyl ketone. As a preferable organic solvent, alcohol is mentioned, for example, More preferably, t-butanol, methanol, ethanol, 2-propanol etc. are mentioned. When bortezomib is dissolved in an organic solvent, the amount of bortezomib used is an amount sufficient to dissolve bortezomib and does not place an excessive burden on subsequent lyophilization. Specific amount of the organic solvent is, for example, 0.03 to 3 mL, preferably 0.1 to 1 mL with respect to 3 mg of bortezomib. It is preferable to reduce the amount of the organic solvent used as much as possible in consideration of environmental load.
The amount of water used in the case of using an organic solvent includes, for example, 5 to 50 parts by weight, preferably 10 to 30 parts by weight with respect to 1 part by weight in total of bortezomib, arginine and hydroxydicarboxylic acid and / or a salt thereof. Part.

After adjusting the volume of the obtained solution to a certain amount with water, sterilization filtration is preferably performed. Sterile filtration can be performed using a sterile filtration membrane, for example, using a 0.22 micron filter.
Subsequently, the sterilized and filtered solution is filled into a vial so as to be a certain amount of bortezomib and lyophilized. The freeze-drying can be performed by, for example, freezing at −25 to −50 ° C. and drying under reduced pressure. Examples of the pressure include a degree of vacuum of 3 to 10 Pa.

3. Storage stability / reconstitution time of freeze-dried preparation Impurities represented by the structural formulas below the increase were confirmed in the storage stability test of the preparation.

  In the test examples of this specification, paying attention to the increase in the impurities A, B, D, E and G, the stability of the freeze-dried preparation was evaluated. In the freeze-dried preparation of the present invention, the increase in impurities is suppressed to a low level. In the freeze-dried preparation of the present invention, the reconstitution time into water is short, for example, 60 seconds or less, preferably 30 seconds or less, more preferably 20 seconds or less.

4). Application of lyophilized formulation The lyophilized formulation of the present invention is used, for example, in the treatment of multiple myeloma. For example, when preparing an injection solution for intravenous administration, 3.0 mL of physiological saline is added to a vial containing 3 mg of bortezomib and dissolved, and then applied to the patient. For example, when preparing an injection solution for subcutaneous administration, 1.2 mL of physiological saline is dissolved in a vial containing 3 mg of bortezomib and applied to the patient.

EXAMPLES Hereinafter, although an Example, a comparative example, and a test example demonstrate this invention further in detail, this invention is not limited to these at all.
<Test method>
(1) Reconstitution test Add 1.2 mL of physiological saline to a vial containing the lyophilized preparation just prepared and shake it to determine the time (dissolution time) until all of the powder of the lyophilized preparation is dissolved. measure. The dissolution time here corresponds to the reconstitution time of the freeze-dried preparation.
(2) pH measurement of injectable solution 3 mL of physiological saline is added to a vial containing a lyophilized preparation to measure the pH of the solution when everything is dissolved.

(3) Storage stability test The freeze-dried preparation filled in a sealed vial is stored at 70 ° C. for 9 days or at 60 ° C. for 3 weeks. Thereafter, 1.5 mL of physiological saline and 1.5 mL of acetonitrile are added to the vial to dissolve everything, and a sample solution is obtained.
The stability of the prepared solution was confirmed as follows. The amount of each related substance and total related substances in each sample solution was measured by the HPLC method. The conditions of the HPLC method are as follows.
Detector: UV absorptiometer (measurement wavelength: 270 nm)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 25 cm was packed with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 30 ° C. Mobile phase flow rate: 1.0 mL / min
Sample injection volume: 20 μL

Mobile phase: composed of solutions A and B.
Solution A: Mix 750 mL of water with 250 mL of acetonitrile and 1 mL of formic acid.
Solution B: Add 800 mL of acetonitrile and 1 mL of formic acid to 200 mL of water and mix.
Transfer of mobile phase: The concentration gradient is controlled by changing the mixing ratio of solution A and solution B as follows.

The peak area of each specimen was measured by the automatic integration method, and the amount thereof was determined by the area percentage method, and the amount of each related substance and the total related substances were determined. Note that the total related substances include all impurities including the impurities A, B, D, E, and G.

Example 1
Preparation of lyophilized preparation containing citric acid 60 mg of bortezomib was dissolved in 10.8 mL of t-butanol at 50 ° C. 400 mg of L-arginine, 256 mg of citric acid hydrate and 96 mg of sodium citrate hydrate were dissolved in 13.2 mg of water for injection at room temperature. The obtained two solutions were mixed, and the volume of the mixed solution was adjusted to 12 mL with water for injection.
The resulting solution was sterile filtered using a sterile filtration membrane (0.22 micron filter) and filled into vials each 1.20 mL. Thereafter, the vial was placed in a freeze dryer and freeze-dried. After completion of drying, the pressure was returned using nitrogen, and the vial was sealed to obtain a lyophilized preparation.

Comparative Examples 1-3
Preparation of freeze-dried preparations Lyophilized preparations of Comparative Examples 1 to 3 were prepared in the same manner as in Example 1 using the components shown in Table 2 in the amounts shown. The preparation of Comparative Example 1 is a preparation described in Patent Document 2, and corresponds to a commercially available Velcade (registered trademark) preparation.

Test example 1
Lysis time of lyophilized formulation and pH of the resulting injection
About the freeze-dried formulation of Example 1 and Comparative Examples 1-3, the above-mentioned (1) reconstitution test and (2) pH measurement of the injection were implemented. The results (dissolution time and injection pH) are shown in Table 3.

The lyophilized preparation of Example 1 dissolved faster than the lyophilized preparation of Comparative Example 1. Moreover, the lyophilized preparations of Comparative Examples 2 and 3 did not dissolve in physiological saline.

Test example 2
Storage stability of freeze-dried preparations The freeze-dried preparations of Example 1 and Comparative Examples 1 to 3 were tested for storage stability at 70 ° C for 9 days and at 60 ° C for 3 weeks. The results are shown in Table 4.

The lyophilized preparation of Example 1 had a smaller increase in total related substances and improved storage stability than the lyophilized preparations of Comparative Examples 1 to 3.

Examples 2-7
Preparation of lyophilized preparation containing citric acid with varying arginine content The lyophilized preparations of Examples 2 to 7 were carried out using 3 mg of bortezomib with L-arginine and citric acid hydrate in the amounts shown in Table 5. Prepared as in Example 1.

Test example 3
Dissolution time of lyophilized preparation containing citric acid and pH of the obtained injection
About the freeze-dried preparation of Examples 2-7, the above-mentioned (1) reconstitution test and (2) pH measurement of the injection were implemented. The results (dissolution time and injection pH) are shown in the lower part of Table 5.
The lyophilized preparations of Examples 2 to 7 dissolved faster than the lyophilized preparation of Comparative Example 1. In particular, the lyophilized formulations of Examples 4 and 5 dissolved faster.

Test example 4
Storage stability of lyophilized preparation containing citric acid The lyophilized preparations of Examples 2 to 7 were tested for storage stability at 70 ° C. for 9 days. The results are shown in Table 6.

  The amount of increase in the total related substances obtained by subtracting the initial amount of the total related substances from the amount of the total related substances after 9 days at 70 ° C. is the lyophilization of Comparative Example 1 in any of the freeze-dried preparations of Examples 3-7. It was less than the increase in total related substances after 9 days at 70 ° C., and the storage stability was more excellent. Moreover, the increase amount of the total related substances of the freeze-dried preparation of Example 2 was equivalent to the freeze-dried preparation of Comparative Example 1.

Examples 8-14
Preparation of citric acid-containing lyophilized preparation with varying citric acid content Using the amounts of L-arginine and citric acid hydrate described in Table 7 to 3 mg of arginine, the lyophilized preparations of Examples 8 to 14 were prepared. Prepared in the same manner as in Example 1.

Test Example 5
Dissolution time of lyophilized preparation containing citric acid and pH of the obtained injection
About the freeze-dried preparation of Examples 8-14, the above-mentioned (1) reconstitution test and (2) pH measurement of the injection were implemented. The results (dissolution time and injection pH) are shown in the lower part of Table 7.
All of the freeze-dried preparations of Examples 2.9 to pH 2.9 to 6.7 dissolved faster than the lyophilized preparation of Comparative Example 1. In particular, the lyophilized formulations of Examples 10-12 dissolved faster.

Test Example 6
Storage stability of freeze-dried preparation containing citric acid The freeze-dried preparations of Examples 8 to 14 were tested for storage stability at 70 ° C. for 9 days. The results are shown in Table 8.

The amount of the increase in the total related substances obtained by subtracting the initial amount of the total related substances from the amount of the total related substances after 9 days at 70 ° C. is the lyophilization of Comparative Example 1 in any of the freeze-dried preparations of Examples 10-14. It was less than the increase in total related substances after 9 days at 70 ° C., and the storage stability was more excellent.
The citric acid content is preferably at least 0.3 to 1 part by weight, more preferably 0.4 to 0.9 part by weight, and still more preferably 0.8 to 1 part by weight of arginine. It turns out that it is 45-0.8 weight part.

Examples 15-19
Preparation of a tartaric acid-containing lyophilized formulation with varying pH. Bortezomib, L-arginine and tartaric acid in the amounts shown in Table 9 (per vial) were added to water for injection and dissolved at room temperature to obtain a solution of pH 4-8. Prepared. The pH was adjusted by increasing the amount of tartaric acid, but the pH was adjusted by adding an aqueous sodium hydroxide solution. Subsequently, in the same manner as in Example 1, sterile filtration, vial filling and lyophilization were performed to obtain a lyophilized preparation.

Test Example 7
Dissolution time of tartaric acid-containing lyophilized preparation The above-mentioned (1) reconstitution test was carried out on the lyophilized preparations of Examples 15 to 19. The result (dissolution time) is shown in the lower part of Table 9.
The freeze-dried preparations of Examples 15 to 19 having a pH of 5 to 8 dissolved quickly, and in particular, the freeze-dried preparations of Examples 16 to 19 dissolved faster than the freeze-dried preparation of Comparative Example 1.
Moreover, the pH of the solution which melt | dissolved the freeze-dried formulation of Examples 15-19 with 3 mL of physiological saline was the same as that of the solution of Table 9.

Test Example 8
Storage Stability of Tartaric Acid-Containing Lyophilized Formulations The lyophilized formulations of Examples 15 to 19 were tested for storage stability at 70 ° C. for 9 days. The results are shown in Table 10.

The amount of the increase in the total related substances obtained by subtracting the initial amount of the total related substances from the amount of the total related substances after 9 days at 70 ° C. is a comparative example in each of the freeze-dried preparations of pH 4 to 8 in Examples 15 to 19 The lyophilized preparation of No. 1 was less than the increase in total related substances after 9 days at 70 ° C., and the storage stability was more excellent.
From the results of Test Examples 5 to 8, the pH of the hydroxydicarboxylic acid-containing lyophilized preparation is preferably about 3.5 to 8, more preferably 4 to 8, and still more preferably about 4.5 to 7.

Examples 20-24
Preparation of freeze-dried preparation containing tartaric acid with varying arginine content Bortezomib, L-arginine and tartaric acid in the amounts shown in Table 11 (per vial) were added to water for injection and dissolved at room temperature to prepare a solution. . Subsequently, in the same manner as in Example 1, sterile filtration, vial filling and lyophilization were performed to obtain a lyophilized preparation.

Test Example 9
Dissolution time of tartaric acid-containing lyophilized preparation The above-mentioned (1) reconstitution test was carried out on the lyophilized preparations of Examples 20 to 24. The result (dissolution time) is shown in the lower part of Table 11.
The freeze-dried preparations of Examples 20 to 24 dissolved quickly, and in particular, the freeze-dried preparations of Examples 20 to 22 dissolved faster than the freeze-dried preparation of Comparative Example 1.
Moreover, the pH of the solution which melt | dissolved the freeze-dried formulation of Examples 20-24 with 3 mL of physiological saline was the same as that of the solution of Table 11.

Test Example 10
Storage Stability of Tartaric Acid-Containing Lyophilized Formulations The freeze stability formulations of Examples 20 to 24 were tested for storage stability at 70 ° C. for 9 days. The results are shown in Table 12.

The amount of increase in the total related substances obtained by subtracting the initial amount of the total related substances from the amount of the total related substances after 9 days at 70 ° C. is the lyophilization of Comparative Example 1 in any of the freeze-dried preparations of Examples 20-24. The formulation was equivalent to or less than the increase in total related substances after 9 days at 70 ° C. and had excellent storage stability.
From the results of Test Examples 3, 4, 9 and 10, the weight ratio of bortezomib and arginine in the lyophilized preparation containing hydroxydicarboxylic acid is preferably about 1: 1.5 to about 1:15, more preferably 1: 1. 7 to 1: 13.3, more preferably 1: 3.3 to about 1:12, and particularly preferably 1: 6.7 to about 1:11.

Comparative Examples 4-8
Preparation of lyophilized preparation using other acids Bortezomib, L-arginine and various acids described in Table 13 (per vial) were added to water for injection and dissolved at room temperature to prepare a solution. Subsequently, in the same manner as in Example 1, sterile filtration, vial filling and lyophilization were performed to obtain a lyophilized preparation.

Test Example 11
Lysis time of lyophilized preparation Comparative examples 4 to 8 and the lyophilized preparation of Example 16 were subjected to the above-described (1) reconstitution test. The result (dissolution time) is shown in the lower part of Table 13.
The lyophilized preparations of Comparative Examples 6 to 8 had a dissolution time of 5 minutes or longer. The other lyophilized preparations of Comparative Examples 4 and 5 and Example 16 dissolved almost immediately.

Test Example 12
Storage stability of freeze-dried preparations The freeze-dried preparations of Comparative Examples 4 to 8 and Example 16 were tested for storage stability at 70 ° C for 9 days. The results are shown in Table 14.

The ascorbic acid-containing lyophilized preparation of Comparative Example 4 produced a large amount of impurities, and the lactic acid-containing lyophilized preparation of Comparative Example 5 produced considerable impurities. Impurities were also produced in the freeze-dried preparations of Comparative Examples 6-8.
That is, a freeze-dried preparation using an acid other than hydroxydicarboxylic acid (for example, citric acid, tartaric acid) as an acid is not sufficiently satisfactory in terms of reconstitution time in water and / or storage stability. I can't understand. On the other hand, in the freeze-drying agent using hydroxydicarboxylic acid such as citric acid and tartaric acid as the acid, as shown in Test Example 3 to Test Example 12, the reconstitution time in water is short, and it is stored. Excellent stability.

  The present invention provides a freeze-dried formulation of bortezomib with excellent storage stability and a short reconstitution time into water.

Claims (6)

  A freeze-dried preparation comprising bortezomib, arginine, and hydroxydicarboxylic acid and / or a salt thereof.   The lyophilized preparation according to claim 1, wherein the hydroxydicarboxylic acid is tartaric acid or citric acid.   The lyophilized preparation according to claim 1 or 2, wherein the weight ratio of bortezomib to arginine is 1: 1.5 to 1:15.   The freeze-dried preparation according to any one of claims 1 to 3, wherein the pH of the solution is 3.5 to 8 when dissolved in 3 mL of physiological saline per 3 mg of bortezomib.   A method for producing a lyophilized preparation, comprising a step of lyophilizing a solution containing bortezomib, arginine and hydroxydicarboxylic acid and / or a salt thereof.   The method for producing a lyophilized preparation according to claim 5, wherein a solution using only water as a solvent is used.